Module - 2

Page 1 of 27 Date printed: 29/10/2009 18:06:40 Date saved: 17/03/2009 16:37:11

ICRI, Bangalore

MODULE 2 ASSIGNMENT GRANT PROPOSAL FOR RAMIPRIL AS FOOD ADDITIVE

SUBMITTED BY LG 02: Shaik imam MENTOR Kirtikrushna Dr. Lincy Jaison Koushik Saritha Zaheeda Srikanth

Institute of Clinical Research India Bangalore


EPSRC Polaris House, North Star Avenue, Swindon, Wiltshire, United Kingdom SN2 1ET Telephone +44 (0) 1793 444000 Web http://www.epsrc.ac.uk/

COMPLIANCE WITH THE DATA PROTECTION ACT 1998 In accordance with the Data Protection Act 1998, the personal data provided on this form will be processed by EPSRC, and may be held on computerized database and/or manual files. Further details may be found in the guidance notes

Standard

PROPOSAL

Document Status: With Owner EPSRC Reference:

Organisation where the Grant would be held (mandatory)

Organisation SKIZ Pharmaceuticals Research Organization Reference:

Division or Department Clinical Research

Project Title (mandatory) [up to 150 chars]

A Randomized, Placebo controlled, double blinded Phase III clinical trial to evaluate the safety and effectiveness of Benopril ( Ramipril + protein drink) in preventing Hypertension in Pre hypertensive subjects

Start Date and Duration (mandatory) a. Proposed start date 14/10/2010 b. Duration of the grant

(months) 36 months

Applicants (mandatory) Role Name Organisation Division or Department How many hours

a week will the investigator work on the project?

Principal Investigator Dr. Kirtikrushna Criterium clinical research

Research and Development 16 hours

Co investigator Dr. Zaheeda Criterium clinical research

Research and Development

16 hours

Statistician Srikanth Biostatistics Research Center (BRC)

Epidemiology and biostatistics

5 hours

Monitor Dr. Saritha Victoria superspecaility hospital Cardiology 16 hours

Physician Dr. Zaheeda KIMS hospital Cardiology 16 hours

Public Communication Training (mandatory)

N.A Objectives (mandatory)

List the main objectives of the proposed research in order of priority [up to 4000 chars]

Primary Objective -To investigate the beneficial effects of Benopril, To prevent and treat hypertension in pre hypertensive patients ( Systolic blood pressure – 120-139mm/Hg and diastolic blood pressure – 80-89 mm/Hg). Secondary Objective - Decrease in LDL levels


Summary (mandatory)

Describe the proposed research in simple terms in a way that could be publicised to a general audience [up to 4000 chars]. Note that this summary will be automatically published on EPSRC’s website in the event that a grant is awarded.

Skiz Pharmaceuticals in collaboration with Cranfield university, U.K, Narayana Hrudayalaya, Bangalore , India and ICRI ,India, is about to conduct a Phase III clinical trial with Benopril ( Ramipril+protein drink) involving 2800 participants in two different countries , namely U.K and India. We wish to conduct this Phase III clinical trial to benefit a vast number of people all over the world suffering from and likely to suffer from Hypertension. Our main intention is to prevent and treat hypertension in pre hypertensive (Systolic blood pressure – 120-139mm/Hg and diastolic blood pressure – 80-89 mm/Hg) subjects and also reduce the cholesterol levels (LDL) to some extent. This helps to cease the progression of hypertension from a Pre Hypertension stage to Stage I and proceed to successive stage. We wish to bring awareness among subjects and also in general population about a preventive approach towards Cardiovascular diseases, where in hypertension is one of the major risk factors. A successful outcome of our research will benefit many people such as general public, students, working class and professionals in the field of Health care and Research. The intended benefit for working class is immense. National Health Services (NHS) in U.K and Health services in India such as Ministry of Health and Family Welfare, Central government health Scheme (CGHS) will be greatly facilitated by this proposed research. By this approach the financial burden of treating Cardiovascular Diseases (CVDs) will be greatly reduced in every country in particular developing countries. On the whole the incidence of CVDs is expected to decrease and thereby increase the life expectancy. The world wide mortality rate due to Cardiovascular Diseases will be drastically reduced.

Academic Beneficiaries (mandatory)

Describe who will benefit from the research [up to 4000 chars].

The main academic beneficiaries include researchers in the field of preventive cardiology and nutritionists for the development of better nutritional products which can be used as drug carriers.

This research aligns with the research interests of staff at Skiz Pharmaceuticals. Professional relationship with our collaborators will yield a high quality results. This in turn will create a pleasant working environment among people involved in research in U.K as well as India.

This trial may open an untraveled path in the successful prevention of major diseases and create insight into developing novel drugs and methods in the management of other diseases. A successful result of our trial will not only benefit the field of cardiology but also other clinical areas. This trial is likely to benefit students, research fellows, researchers, universities, institutions in the field of Medicine and Health. We are looking forward to publish our successful results in high impact journals such as nature, National medical journal of India, British Medical Journal, and medical newspapers such as Medical Express, seminars, lectures, and conferences. Such exposures will also ensure prestigious publicity for SKIZ, Narayana Hrudayalaya, ICRI, India ,Cranfield University and the investigators Our potential beneficiaries may include governments, both in India and U.K, as well as other countries, general public and patients worldwide with cardiovascular diseases.


The most interesting part of the research is that it is on a completely new field of preventive cardiology and would make a valuable addition to this discipline.

Impact Summary (mandatory)

Impact Summary (please refer to the help for guidance on what to consider when completing this section) [up to 4000 chars]

The main aim of this research is to reduce the risk of CVD by the use of the drug Ramipril through a healthy and nutritious protein powder as a carrier for the drug. As mentioned before this research would help reduce the risk of CVD by the reduction of hypertension and bad cholesterol levels to some extent.

By publishing our results in leading medical and scientific journals, newspapers, conducting lectures, workshops, we wish to draw the attention and create awareness among wide range of academic and non- academic audiences including general public, government bodies, Non Government Organizations (NGOs), charities etc. for the benefit of mankind and to improve the quality of life.

This would help spread the message of our product in the medical circles and hence help the sales of the product.

The developed product is one of its kinds hence there exists a huge potential with respect to commercial exploitation. The product is being manufactured in collaboration with Skiz pharmaceuticals and is expected to raise the share price of the company by about 35% through its sales in the first quarter itself.

Skiz pride in having a world class distribution facilities which will help the product reach every corner of the country and make it available to the general public.

Before the launch of the product into the market we are planning to conduct several customer reach out programs at different parts of the country in which we would be educating the participants about hypertension and other risk factors leading to CVD’s and in the process educate them about our product.

This research program is conducted with the help of Cranfield University, Bedford, UK in collaboration with Institute of Clinical Research (India). (ICRI) and Narayana Hrudayalaya. Cranfield University is one of the premier institutes in the United Kingdom and a pioneer in engineering, defence and medical research. They play an important role in ethical aspects of the trial and constitute our IRB. Our previous project was Phase III clinical trial conducted by Skiz and Cranfield University in patients with non- small cell lung cancer (NSCLC) to compare and analyze the clinical benefits versus the clinical risks in patients treated with


combination chemotherapeutic drugs Cisplatin plus Pemetrexed and Cisplatin plus gemcitabine. Our collaborators Narayana Hrudayalaya is one of the leading Cardiac hospitals in INDIA and also one of the world’s largest pediatric heart hospitals. It is known for being highly efficient, excellent patient management and care. Public will be trained through highly qualified and well experienced professionals regarding the beneficial effects of Benopril in the prevention and treatment of hypertension in Pre Hypertensive individuals. We intend to conduct seminars, public workshops, training programmes, lectures to create awareness in the public with respect to Benopril. Door to door distribution of pamphlets and distribution of posters to National health service centres, General practitioners, hospitals, clinicians, pharmacies, medical distributors, nurses, paramedics will be undertaken. Promotion of Benopril through advertisements in electronic media, news paper articles, radio etc will be given prime importance.


Summary of Resources Required for Project Financial resources

Summary fund

heading

Fund heading

Full economic Cost

EPSRC contribution

% EPSRC contribution

Directly Incurred Staff £16,22,700.00 £12,98,160.00 80

Travel & Subsistence £25,75,500.00 £20,60,400.00 80

Equipment £60,000.00 £48,000.00 80 Other Costs £2,30,516.00 £1,84,412.00 80 Sub-total £44,88,716.00 £35,90,972.00 Directly Allocated Investigators £2,10,516.00 £1,68,413.00 80

Estates Costs £31,68,000.00 £28,34,400.00 80

Other Directly Allocated

£1,47,000.00 £1,17,600.00 80

Sub-total £35,25,516.00 £28,20,412.00 Indirect Costs

Indirect Costs £1,25,56,400.00 £1,00,45,120.00 80

Exceptions Staff £30,000.00 £30,000.00 100 Other Costs £51,10,000.00 £51,10,000.00 100 Sub-total £51,40,000.00 £51,40,000.00 Total £2,57,10,632.00 £2,15,96,504.00

Summary of staff effort requested Months Investigator Co investigator

36 months 21 months

Researcher N.A Technician 23 months

Other Statistician Monitor

3 months 6 months

Visiting Researcher

0

Student N.A

Total 89 months

Research Council Facilities

£ 0


Joint Proposals

Complete this section if more than one organization is submitting an EPSRC proposal form for this project. Is this part of a joint proposal? Are you the lead RO? Joint reference

Research Councils / MoD Joint Research Grants Scheme (JGS)

If MoD/DSTL has indicated that they are prepared to provide support for this proposal if successful, please indicate the percentage level of this support and MoD/DSTL contact details.

Percentage funding indicated by DSTL DSTL contact

DSTL Reference (a letter providing this reference is attached with the Case for Support)

Other Support

Details of support sought or received from any other source for this or other research in the same field.

Awarding Organization

Awarding Organization’s Reference

Title of project Decision Made (Y/N)

Award Made (Y/N)

Start Date

End Date

Amount Sought/Awarded (£)

Related Proposals Proposal is related to a previous proposal to EPSRC Reference Number How related?


Staff

Directly Incurred Posts

EFFORT ON PROJECT

Role Name /Post Identifier Start Date

Period on

Project (months)

% of Full Time

Scale Increment Date

Basic Starting Salary

London Allowance

(£)

Super-annuation and NI (£)

Total cost on grant (£)

Monitor Monitor (2) 14/11/2011 21 months 21/12/2011 £50,000 £1,65,000 Project manager Project manager 14/10/2010 36 months 14/10/2011 £72,000 £2,37,600 Medical advisor Medical advisor 21/11/2011 21 months 25/02/2012 £28,000 £92,400 Statistician Statistician (2) 01/04/2013 3 months 17/05/2012 £14,000 £42,000 CRA CRA(2) 14/10/2010 36 months 14/10/2011 £12,000 £73,800 CRC CRC(8) 26/11/2010 36 months 14/10/2011 £10,000 £1,47,600 Lab technician Lab technician(8) 21/11/2011 25 months 15/10/2011 £45,000 £1,53,600 Nurse Nurse (32) 21/11/2011 25 months 15/10/2011 £38,400 £5,70,900 Total £14829000

Exceptions

Role Name /Post Identifier /Institution Start Date London Allowance (£)

Fees Stipend


Travel and Subsistence Destination and purpose Total £ UK & India For the project finalization, training and auditing 2575500

Total £ 2575500

Equipment (the cumulative value of equipment over £50,000 will be treated as an exception)

Description Country of Manufacture

Delivery Date

Basic price £

Import duty £ VAT £ Total £

sphygmomanometer France 10/09/2010 980 20 280 1280

Total £ 1280

Other Directly Incurred Costs Description Total £ Investigator Site training Accountant Recruitment

210516 20000 29760

700000 Total £ 960276

Other Directly Allocated Costs Description Total £ Co-investigator (UK) Co-investigator (India) CRA(UK) CRA(INDIA) Project Manager CRC (8) Medical Advisor Stastician Lab technician(2) Nurses(32) Electricity Telephone bills Stationary

147600 79200 39600 34200

237600 147600

92400 42000 33600

570900 57600 86400

3000 Total £ 1571700

Research Facilities/Existing Equipment Description Total £ A central lab for assessing the blood samples 1264000

Total £ 1264000

Animal Costs

Animal Species

Type and Microbiological Quality

Genetically Altered?

No. Purchased

Average Cost

per Animal

(£)

No. Bred

Average Cost

per Animal

(£)

Maintenance duration (weeks)

Weekly Maintenance

costs per Species (£)

Total Cost

£

Total £ 0

Research Council Facilities

Details of any proposed usage of national facilities Name of Facility Units Cost £ Total £ 0


Project Partners: details of partners in the project and their contributions to the research. These contributions are in addition to resources identified above.

Name of partner organisation

Division or Department Name of contact

Direct contribution to project Indirect contribution to project

Description Value £ Description Value

£

cash use of facilities/ equipment

equipment/materials staff time secondment of staff other other Sub-Total Sub-Total Total Contribution Total Contribution from all Project partners £0

OTHER INFORMATION

Reviewers (mandatory)

1 Name Organisation Division or Department Email Address

Dr.Lincy Jaison ICRI- Institute of Clinical Research Clinical Research [email protected]

Dr.Jeff Newman Cranfield Uniuversity Clinical Research [email protected]

mailto:[email protected]


COMPANY PROFILE - SKIZ PHARMACEUTICALS Headquarters: 15th Avenue, Anderson road, Cranfield, Bedford, UK. Manufacturing units: SKIZ Pharmaceuticals has two manufacturing units. One is located in the Hertfordshire and the other in Bangalore. A clinical development centre in Bedfordshire, a fully equipped Clinical Research Lab in Bangalore (India) with a capacity to conduct clinical trials involving up to 200 subjects and a central laboratory located in Delhi. Collaborators: Cranfield University, Narayana Hrudayalaya, ICRI (India). Introduced technologies: Preme Resuscitation System (PRS) Current work: Research project involving the possible use of cardiac drug Ramipril as a food additive. In this study we have introduced Ramipril into a non-alcoholic, sugar free protein drink, which is suitable for everyone. It is a known fact that proteins are vital nutrients to our body. Unlike fats and carbohydrates proteins are not stored in the human body, hence proteins needs to be supplied every day. The benefits of proteins can be obtained from sources like healthy protein drinks. We have tested our Benopril protein drink with ramipril in pre-clinical studies and ensured that it is nutritious, safe and has added benefits of Ramipril. This drink has also proven to be very effective, efficacious and easily digested in Phase I and Phase II clinical studies. Ingredients Whey Protein, Rice Protein, Flavoring agent – Banana Flavor, Colouring agent – Approved by Food and Drug Administration (FDA), Zinc, Copper, Starch, Coated crystalline ramipril powder particles [2]. Benopril protein powder is packed in little sachet and when mixed with a glass of water (250 ml) is ready to be consumed as drink. Patients are advised to use one sachet a day [3]. Food – Drug interactions This formulation of orally administered ramipril does not have any adverse food effect. In this dosage form a substantially unaltered extent of drug absorption is seen, which can be defined as the area under the curve of a plasma drug concentration against time curve. Rapid disintegration of Ramipril in the drink, improves the availability of the drug for absorption. Disintegrants such as starch have been included to ensure rapid dissolution. Individually coated crystalline ramipril powder particles have greater stability against decomposition into ramipril – DKPs and ramipril-diacids during storage. They also maintain ramipril potency over extended shelf-life. Bioavailability and variability among subjects is also greatly reduced [2]. Zinc depletion is noted in subjects on long term ramipril, in preclinical, phase I and phase II clinical studies. Therefore zinc is incorporated. Copper is added to avoid any zinc induced copper-deficiency [4].


1. PREVIOUS RESEARCH AND TRACK RECORD

SKIZ - Is a leading organization in advanced scientific and therapeutic breakthroughs. Our researchers and scientists have been dynamically involved in research and development to alleviate pain and suffering for over more than a decade. With our combination of scientific expertise, unparalleled technology, talent and dedication we have been able to develop, discover, safest, newest, most innovative, valuable medicines and devices to prevent, intercept, and treat some of the most challenging, aggressive and life threatening diseases. Achievements Our development of the drug “Ramipril” has led to significant decrease in mortality of cardiac patients. It’s wide range of therapeutic benefits and safety has improved the wellness and quality of life. ESPRC Funded projects. Our previous EPSRC funded project include - Preme Resuscitation System(PRS) developed by Skiz which is one of our most recent breakthrough technology in Neonatal resuscitation with effective and reliable airway management. PRS is now recognized and supported by National Health Service (NHS) and widely used in U.K and has greatly reduced the neonatal mortality. We have conducted clinical trials both as an individual organization and with Cranfield University meeting global standards. NON ESPRC Funded Projects Phase III clinical trial was conducted by Skiz and Cranfield University in patients with non- small cell lung cancer ( NSCLC) to compare and analyze the clinical benefits versus the clinical risks in patients treated with combination chemotherapeutic drugs Cisplatin plus Pemetrexed and Cispatin plus gemcitabine [6].


This study was funded by the Macmillan Cancer Support and the study showed that patients with advanced NSCLC had superior survival without toxicity when treated with cisplatin and pemetrexed, when compared with patients treated with cisplatin and gemcitabine. Cisplatin/pemetrexed was convenient to administer and had good tolerability than cisplatin/gemcitabine. Combination of Cisplatin/premetrexed is now increasingly used in many countries including U.K in the treatment of NSCLC. This combination is given as first line of treatment in U.K. Better tolerability and decreased toxicity has led to improvement in patients quality of life. Preclinical Data Ramipril is an angiotensin converting enzyme (ACE) inhibitor, ACE inhibitor lowers the production of angiotensin II, therefore relaxes the arterial muscles and allows the heart to pump blood more easily, in other words Ramipril is a vasodilator. To ensure the safety and efficacy of Ramipril as food additives we conducted a trial in 80 adult rats with Benopril Protein Drink the trial was approved by veterinary council of India in accordance with good Clinical practice the rats were administered Benopril,which shows 94% cardiac improvements and found to be safe. Phase I clinical trial The main aim of phase 1 clinical trial was to evaluate the safety of a new food product, which contains Ramipril. Ramipril is an ACE inhibitor which act as a cardio protective. Phase 1 trial was a single centric open label trial which was conducted at Skiz lab Bangalore, approved by Institute of Clinical research India (ICRI), 70 healthy volunteers participated in the trial. Subjects were selected following the inclusion and exclusion criteria. Informed consent was obtained. Subjects were administered Benopril protein drink and their biological samples were taken and tested to obtain the pharmacological data. Phase I results showed Benopril protein drink as 96% safe. Phase II Clinical trial The aim of Phase II clinical trial was to assess safety, efficacy, bio-availability. Phase II trial was a multi centric double blinded randomized trial, which was conducted at Tata memorial hospital Delhi and Victoria hospital Bangalore, The trial was conducted by experienced PI, Dr. John Machles and Dr. Kirtikrushna with good protocol and GCP. 120 Pre hypertensive and Stage I hypertensive patients were included in the trial after obtaining the written informed consent. Placebo was used as a comparator. 120 patients were divided in two groups, one group received placebo and other group the study product. The results were compared accordingly, The patient data showed that the new drug has Safety- 96%, Efficacy- 85%, Bioavailability -74.6%


2. DESCRIPTION OF THE RESEARCH

BACKGROUND: Cardiovascular diseases (CVD) play a major role in mortality and growing health problems which many countries are facing today. Among the other CVD, hypertension plays an important role in the development of CVD.CVD is associated with multiple risk factors such as tobacco smoking, obesity, hypertension and diabetes, increased blood glucose levels, LDL levels which has added to the rise in mortality [5]. Hypertension is associated with other life threatening diseases such as diabetes, atherosclerosis, and myocardial infarction. According to WHO report 2005, the mortality rate is high in United State of America and in European countries. The predicted mortality rate in India is about 2.6 millions in year 2020, nearly 1 in every 2.9 deaths are due to Coronary Heart Diseases (CHD). The patients who are suffering from hypertension is estimated to be 73,600,000 and steadily rising. Ramipril (ACE inhibitors) is one of the major drugs used in the treatment of hypertension.The antihypertensive action of the Ramipril is, it mainly inhibits Angiotensin Converting Enzyme. The Ramiprilat is an active metabolite of Ramipril formed in liver, which binds with Angiotensin converting enzyme and prevents formation of potent vasoconstrictor Angiotensin II. This enzyme – inhibitor complex has slow rate of dissociation which leads to longer action and high potency. Ramipril not only helps in prevention of hypertension but also reduces the risk of myocardial infarction and stroke [3]. Pharmacokinetic and Pharmacodynamic properties of Ramipril The route of administration of the Ramipril is through oral, 50 – 60 % of drug is well absorbed and remaining 40 % is excreted through urine. The bioavailability of the Ramipril is 28 % and the half life is about 2-4 hours. The serum protein binding of Ramipril is about 73% . Dose requirement Effective dose: 2.5mg Adverse reaction Cough malaise, dry mouth, polyuria, constipation Contraindication Allergic to Ramipril, Pregnancy Monitoring parameters Systolic/diastolic blood pressure and Cholesterol levels – LDL, HDL,VLD


Ø RESEARCH HYPOTHESIS AND OBJECTIVES

Title of research: A Randomized, Placebo controlled, double blinded Phase III clinical trial to evaluate the Safety and effectiveness of Benopril( Ramipril + protein drink) in preventing Hypertension in Pre hypertensive subjects. Aim: The aim of this study is to determine the safety and efficacy of Benopril to prevent hypertension in pre hypertensive patients. Objectives:

o Primary objective: To investigate the beneficial effects of Benopril, and to prevent and treat hypertension in pre hypertensive patients ( Systolic blood pressure – 120-139mm/Hg and diastolic blood pressure – 80-89 mm/Hg).

o Secondary objective: Decrease in LDL levels

Ø PROGRAM AND METHODOLOGY

Study centers: Total : 8 sites in 4 centres in India and U.K. o Narayana Hrudayalaya, Bangalore. o Heart of England, Bedford, UK o London Bridge Hospital, London, UK o KIMS Hospital, Hyderabad. o TATA memorial hospital, Bangalore o Aston Hall Hospital, London, UK o SCB medical college, Hyderabad o Alexandra Hospital, Bedford, UK

Study population: Male and female between the ages of 25 – 45 years. Subject condition: Healthy and Pre-hypertension Sample size: 2800 Expected duration of study: 36 months. Subject recruitment period: 2 months. Expected trial starting date: 14/10/2010. Expected study completion date: 19/07/2013 Recruitment of subjects: subjects are recruited through

1. Advertising in daily news papers and weekly magazines, 2. Through hospitals. 3. Through intermediaries.

All subjects will be recruited through the informed consent process. Ethics committee approved informed consent forms both in English and local languages will be used . Patients will be given relevant information regarding the preparation and consumption of protein drink.


Blood pressure monitoring: Blood pressure will be measured during recruitment process(inclusion criteria) to determine the eligibility of the subject and record baseline readings. Inclusion criteria:

1. Both males and females of age between 25 – 45 years 2. Healthy and Pre hypertensive subjects.

Exclusion criteria:

1. Malignant hypertension 2. Congestive heart failure 3. Myocardial infraction 4. Impaired hepatic function 5. Pregnancy 6. History of Angiodema 7. Heavy drinkers

Study type: Interventional Study Design: Phase III trial Allocation: Randomized (Method of randomization – computerized), parallel Method of randomization – computerized

• Control: Placebo control

• Placebo: Inert

• Masking: Double blinded

Study Arms: Two Arms

1. Active: - Drug : Benopril protein drink. 2. Control :- Placebo

Methodology: This is a prospective, randomized, parallel, double blind, and multi-centric clinical trial. During the recruitment period recruitment period – 2 months, both men and women between the age of 25 to 45 years will be selected. Estimation of Sample size: For the estimation of sample size Systolic blood pressure is considered because it is having the most Standard Deviation. If increase in standard deviation is taken into consideration to calculate the sample size, then the sample for the other variable is also taken into consideration namely Diastolic blood pressure. From the previous studies it has been observed with Ramipril that decrease in mean systolic blood pressure is 11.2mm/Hg with a Standard deviation of 5.5 mm.[1]


It is assumed Ramipril + Protein powder treatment, the decrease in systolic blood pressure to be 12.2mm/Hg, with a Standard deviation of 5.0mm. The sample size is estimated based on 1% significance level and 90% power. The following formula is used for the required sample size for each treatment group. ( Zα – Z1-β)2 ( σ1 2 + σ2 2 )

(X 1 – X 2) 2

Zα = 2.58 for 1% significance level Z1-

β = 0.920 for 80% power X = 11.2; X = 12.2; σ1 =5.5; σ2 = 5.0 Therefore sample size = 350 in each centre. 2800 subjects will be recruited to 8 sites after screening and written informed consent is obtained. Ethics committee approved Informed consent form in English and Local languages will be used and the consent will be obtained after subjects are explained about the relevant information regarding the trial. Blood pressure and cholesterol levels will be recorded for baseline readings and the subjects will be selected according to inclusion criteria. The subjects and the investigators will be blinded by assigning codes to the subjects. The subjects are randomly (computerized randomization) allocated into 2 groups i.e. active group and control group of 1400 each. The active group will receive Benopril and control group will receive the placebo. In order to blind the subjects both the active drug and placebo will be packed in similar sachets and dispensed to the participants during each visit. The contents of the sachet are to be mixed with 250ml of water and made into a drink. The subjects are advised to consume this drink at bed time. Subjects will have twice weekly visits for a period of 21 months. Blood pressure will be monitored and recorded twice a week and cholesterol levels will be checked and recorded once a month. ANOVA -statistical analysis software will be used for the statistical analysis.

Trial Outcome: Primary outcome measures: To demonstrate the efficacy and safety of Benopril in subjects with pre hypertension by bed time administration. Secondary Outcome: To demonstrate that Benopril has an effect on cholesterol levels. End points: 1. Primary End Point : Treat and prevent hypertension in pre hypertensive subjects.

2. Secondary End Point : To decrease the levels of LDL.

=


Ø RELEVANCE TO ACADEMIC BENEFICIARIES

SKIZ have a highly experienced staff in the investigator’s department. This proposal articulates with the research interests of many of our staff. A successful outcome in this research will turn the management of cardiovascular diseases into focusing on the preventing aspect. Cranfield University in U.K, renowned for its excellent track record and breakthrough research, has expressed interests in collaboration to conduct this trial. Our teams of Co-I and PI have good understanding and productive relationship with other members at Cranfield on this subject. This trial may open an untraveled path in the successful prevention of major diseases and create insight into developing novel drugs and methods in the management of other diseases. We are looking forward to publish our successful results in high impact journals such as nature, National medical journal of India, British Medical Journal, medical newspapers such as Medical Express, seminars, lectures, conferences. Such exposures will also ensure prestigious publicity for SKIZ, Cranfield University and the investigators. This trial is likely to benefit students, research fellows, researchers, universities, institutions in the field of Medicine and Health. Our potential beneficiaries may include governments, both in India and U.K, as well as other countries, general public and patients worldwide with cardiovascular diseases. We intend to make a significant contribution in the field of management of cardiovascular diseases. Successful outcome will benefit researchers working on congestive cardiac failure, myocardial infarction, Angina, coronary artery diseases. Achieving our secondary objective will benefit researchers working in cardiology, diabetology, Nutritional Health, weight management.


3. IMPACT PLAN Why is the research conducted? It is a known fact that CVDs are one of the major diseases. An independent study suggests that four out of every ten Indians are affected with a CVD or are at the risk of getting a CVD. This can mainly be attributed to the change in lifestyle, reduced manual work and unhealthy eating habits. The main aim of this research is to reduce the risk of CVD by the use of the drug Ramipril through a healthy and nutritious protein powder as a carrier for the drug. Who will benefit from the research? • Academic beneficiaries: The main academic beneficiaries include researchers for further

research activities in the field of preventive cardiology and nutritionists for the development of better nutritional products which can be used as drug carriers. The most interesting part of the research is that it is on a completely new field of preventive cardiology and would make a valuable addition to this discipline.

• Benefit to general public: As mentioned earlier this combination would help reduce the risk of CVD by the reduction of hypertension and would be of great help to the working class (especially to the corporate work force) leading to their increased productivity. On a whole it is expected to decrease the incidence of the CVD’s by 25% thereby increasing the life expectancy.

• Commercial benefit: The developed product is one of its kinds hence there exists a huge potential with respect to commercial exploitation. The product is being manufactured in collaboration with Skiz pharmaceuticals and is expected to raise the share price of the company by about 35% through its sales in the first quarter itself.

How will we ensure that the impacts reach the concerned parties? • The research is planned to be published in all leading science journals and we are planning to

conduct a series of conferences with leading cardiologists and nutrition experts for their useful feedback about the product.

• This would help spread the message of our product in the medical circles an hence help the sales of the product.

• Apart from this we are planning to conduct several product workshops to educate the nutritionists and doctors about the product. We would be getting useful data about many aspects of preventive cardiology which would be discussed in the workshops.


• We are planning to release the product in collaboration with Skiz pharmaceuticals. Skiz pride in having a world class distribution facilities which will help the product reach to every corner of the country and make it available to the general public.

• Before the launch of the product into the market we are planning to conduct several customer reach out programs at different parts of the country in which we would be educating the participants about hypertension and other risk factors leading to CVD’s and in the process educate them about our product.

COLLABORATION: This research program is conducted with the help of Cranfield University, Bedford, UK in collaboration with Institute of Clinical Research (India). (ICRI) and Narayana Hrudayalaya. Cranfield University is one of the premier institutes in the United Kingdom and a pioneer in engineering, defence and medical research. ICRI is one the first institute in India to provide a structured course in clinical research and has achieved several milestones in a short period of time and has emerged as one of the top institutes in India. They play an important role in ethical aspects of the trial and constitute our IRB. Our previous project was Phase III clinical trial conducted by Skiz and Cranfield University in patients with non- small cell lung cancer (NSCLC) to compare and analyze the clinical benefits versus the clinical risks in patients treated with combination chemotherapeutic drugs Cisplatin plus Pemetrexed and Cisplatin plus gemcitabine. Our collaborators Narayana Hrudayalaya is one of the leading Cardiac hospitals in INDIA and also one of the world’s largest pediatric heart hospitals. It is known for being highly efficient, excellent patient management and care.


4. WORK PLAN


5. JUSTIFICATION OF RESOURCES

RESOURCES ROLES JUSTIFICATION

PRINICIPAL INVESTIGATOR

Principle investigator is the person responsible for the scientific and technical aspects of the trial. He is also responsible for the overall coordination during the clinical trial

The main responsibility of principle investigator is to provide medical care to all patients and to tackle any untoward response during the trial. Their leadership activities, experiences and their cooperation have made the recruitment success.

CO-INVESTIGATOR

Co investigator is the person who is involved in the trial and supports the PI with the performing procedures and monitoring

Assist the principle investigator and holds responsibility in his absence

MONITOR Monitoring the clinical trial The main responsibility is to oversee the progress of the clinical trial

STATISTICIAN Plan prepare implement and thorough analysis of the clinical trial data

A biostatistician is needed for the sample size calculation

CRA Monitors the progress of the trial Monitoring and collection of data at different sites

CDM

Data management

Monitors the entire process of the data management and is to be computerised.

LAB TECHNICIAN sample collection and analysing of the sample samples collected from the participants at regular intervals must be analysed by a experienced lab technician in a well equipped lab

HOSPITALS

Patients must be subjected to observation under trained medical staff. so hospitals is a must

To record any kind of physiological or biochemical imbalance occurring in the participants, a hospital is required

TRAVEL AND TRANSPORTATION

For transportation purpose For the transportation of samples and participants where the participants are reimbursed for the same


6. CURRICULUM VITAES

DR.KIRTIKRUSHNA MBBS, M.D, PHD email : [email protected] PROFESSIONAL EXPERIENCE

Instructor in Medicine (cardiology), 1970-74 associate professor of medicine(cardiology)

Associate professor University of Gandhi(cardiology)hospitals, india 1974-2001

Medical director,IHG ECG services,LDS hospital,Hyderabad,India

EDUCATION

MBBS : University of Gandhi hospitals,Hyderabad,India,1961

MD : university of osmania,delhi,1966

Fellowship:cardiology,1969-71,university of Gandhi hospitals,Hyderabad,India

Dr. ZAHEDA email:- [email protected] EDUCATION

MBBS ATLS ACLS May 1998 NTR UHS,India

March 2007,Trinidad & Tobago

May 2008,florida,USA,july 2010 Trinidad and Tobago

EMPLOYMENT

HISTORY

14-9-2009 to till to date 19-9-2006 to 30-9-2009 2-6-00 to 4-7-02 house officer,A&E dt,animal healthfacility,t&t

house officer,A&E dept,POS general hospital,t&t

house officer,siddarth hospital,nellore,India

DR.KAUSHIK email : [email protected] PROFESSIONAL EXPERIENCE

Private Practice 1982 – Present

Student Volunteer, 1994 india Department of Justice, Health Fraud Unit,INDIA

EDUCATION D.O., College of Osteopathic Medicine and Surgery

B.S., Illinois State University, Bloomington, Illinois - 1975 Biology

DR.SARITHA email : [email protected] PROFESSIONAL EXPERIENCE Experience in research : 1994 to till date : Johns Medical Center, newyork Done research on specific protein identified to dephosphoryte cell fat EDUCATION MBBS : SV.university,trupati,india

PRINCIPLE INVESTIGATOR

INVESTIGATOR

CO INVESTIGATOR

MONITOR





MS.SAPNA JHA email : [email protected]

PROFESSIONAL EXPERIENCE : Worked as a staff nurse in ICCU in Bollineni Hospital from 06-03-09 to 30-4-10.

EDUCATION : B.sc nursing degree, narayana nursing college

MR.SRIKAMTH email: [email protected] PROFESSIONAL EXPERIENCE project trainee in Department of Cardiology, KEM hospital, Mumbai.2009-10.

EDUCATION : BHMS : Maharashtra University: 2002-2007….PG Diploma in Emergency Medical Service : Ruby Hall Clinic, Pune

MR.P.UMESH KUMAR email:[email protected]

PROFESSIONAL EXPERIENCE: Working as CRC in Shruti Hospital &research center of Orthopaedics, Nagpur. Worked in Spectrum Clinical Research Pvt.Ltd, Mumbai.

EDUCATION : Master in biochemistry with 69% in 2006 - Shukla University, Raipur.

MR.SHAIKIMAM email: [email protected]

PROFESSIONAL EXPERIENCE Working as a project manager in Apollo hospitals, Chennai

EDUCATION MBA. In health care management

CRA

CRC

PROJECT MANAGER

NURSE




REFERENCE:-

1. http://hyper.ahajournals.org/cgi/content/full/54/1/40 accessed on 20th sep 2010).

2. http://www.freshpatents.com/Stabilized-individually-coated-ramipril-particles-compositions-and-methods-dt20060720ptan20060159742.php accessed on 20th sep 2010

3. http://www.sumobrain.com/patents/wipo/Ramipril-formulation/WO2007028978.html accessed on 22nd sep 2010

4. http://www.healthkey.com/a-z/hw-hn-1480007,0,6750507.story accessed on 25th sep 2010).

5. http://www.theheart.org/article/926425.do accessed on 27th sep 2010).

6. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy –naïve patients with advanced –stage non – small – cell lung cancer.Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D.

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Scagliotti%20GV%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Parikh%20P%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22von%20Pawel%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22von%20Pawel%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Biesma%20B%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Vansteenkiste%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Manegold%20C%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Serwatowski%20P%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Gatzemeier%20U%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Digumarti%20R%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Zukin%20M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lee%20JS%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mellemgaard%20A%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Park%20K%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Park%20K%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Patil%20S%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rolski%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Goksel%20T%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22de%20Marinis%20F%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Simms%20L%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sugarman%20KP%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Gandara%20D%22%5BAuthor%5D


Group Members: Guide

1. Imam Jaffer Dr. Lincy jaison 2. Kirtikrushna 3. Kaushik 4. Saritha 5. Srikanth 6. Jaheeda

Sl no Topics of Discussion Members

01. Ø Discussion on the aims and objectives Ø Working on the study design Ø Discussion on the protocol development goals Ø Setting the primary and secondary objectives Ø Discussion on follow up of the previous

meeting held Ø Working and discussions on the protocol draft

and methodology

All members

02. Purpose of meeting

Ø Discussion on areas to be improved upon and

worked on Ø Setting a significant,strong and effective clinical

trial plan Ø Working on the drawbacks of the presentation

presented on 23/09/2010

All members

Agenda

ICRI, Bangalore


Date Time Topic of Discussion Present Members

Meeting Held

Result

20/09/2010 11am-11.15am

Discussion On Ramipril, PK,PD All Members Room no -1 Web search about the topic

11.15am-11.30am

Food product All members Room no -1 Decided the Food Product

11.30am-11.45am

Work Distribution among members All members Room no -1 Agreed on Individual responsibility

27/09/2010 10.30am-10-45am

Selection of Sample Size, Chose site, All members Room No-4 Took biostatistician help

10.54am-11am

Study Design All members Room No-4 Planned study design

11am -11.15 Work plan All members Room No-4 Designed work plan

4/10/2010 10.30am-10.45am

Budget, Editing, Proof Reading All members Room No-1 Planned Budget

10.45am-11.00am

Draft submission, Power point preparation.

All members Room No-1 Noted down points for presentation

11.00am -11.15am

Filling of EPSRC, Prepare the Final Draft. All members Room No-1 All members agreed on Individual responsibility

Minutes of Meeting

ICRI, Bangalore

Documents

Module - 2